1. Introduction
The following description includes information that may be useful in understanding the present invention. It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
2. Background
For the past several decades, scientists and engineers have researched and developed techniques for the delivery of pressurized contents, such as aerosols, for a wide range of applications. Today, such techniques are a part of everyday life as there are thousands of products packaged in aerosol cans—everything from air fresheners to insect repellants to paint to deodorant to hair spray to cooking oil to medicines. The most common techniques for generating aerosols involve the use of a compressed propellant such as methylchloroform or chloro-fluoro-carbon (CFC) to entrain the material desired to be delivered. Aerosol cans (typically made of metal) come in many shapes and sizes but all work on the same basic principle: one high-pressure fluid (or gas) forces another fluid (or particles) through a nozzle. An aerosol can contains one fluid that boils well below room temperature (called the propellant) and one that boils at a much higher temperature (called the product). The product is the substance actually intended to be delivered—the hair spray, insect repellent, paint, or medicine, for example, while the propellant is used to get the product out of the can.
There are two ways to configure this aerosol system. In the simpler configuration (compressed-gas system), liquid product is poured into the container, the can is sealed, and then a gaseous propellant is pumped into the can at high pressure through a valve system built into the container. A typical configuration of this sort for delivering a product as a compressed gas aerosol is as follows: a long plastic tube runs from the bottom of the container up to a valve system at the top of the can. The valve has a small, depressible headpiece with a narrow channel running through it. The channel runs from an inlet near the bottom of the headpiece to a small nozzle at the top. A spring pushes the head piece up, so the channel inlet is blocked by a tight seal. When the headpiece is depressed, the inlet slides below the seal, opening a passage from the inside of the can to the outside. The high-pressure propellant gas drives the liquid product up the plastic tube and out through the nozzle. The narrow nozzle serves to atomize the flowing liquid, break it up into tiny droplets that form a fine spray.
In the second and more popular aerosol system (liquefied-gas system), the propellant is a liquefied gas. This means that the propellant will take liquid form when it is highly compressed, even if it is kept well above its boiling point. Since the product is liquid at room temperature, it is simply poured in before the can is sealed. The propellant, on the other hand, must be pumped in under high pressure after the can is sealed. When the propellant is kept under high enough pressure, it cannot expand into a gas. It thus stays in liquid form as long as the pressure in the container is maintained. While aerosol devices that use a liquefied-gas system may be structurally equivalent to those used by a compressed-gas system, devices that use liquefied-gas system function differently when the headpiece is depressed. In the liquefied-gas system, when the valve is opened, the pressure on the liquid propellant is instantly reduced. With less pressure, it can begin to boil. Particles break free, forming a gas layer at the top of the can. This pressurized gas layer pushes the liquid product, as well as some of the liquid propellant, up the tube to the nozzle. Some such devices, such as spray-paint cans, have a ball-bearing or similar component inside. Upon shaking, the ball bearing helps to mix the propellant and the product phases, so that the product is ejected from the device as in a fine mist. When the liquid (composed of both propellant and product portions) flows through the nozzle, the propellant rapidly expands into gas. In some aerosol systems of this type, this action helps to atomize the product, forming an extremely fine spray. In other designs, the evaporating propellant forms bubbles in the product, creating foam. The consistency of the expelled product depends on several factors, including: the chemical makeup of the propellant and product; the ratio of propellant to product; the pressure of the propellant; and the size and shape of the valve system. Manufacturers produce a wide variety of aerosol devices by configuring these elements in different combinations. While widely used, such aerosol devices remain somewhat limited because: the particles dispersed are too large for certain applications; currently there is no effective way of monitoring the amount of contents remaining in the can at any given time; and the most widely used conventional propellants have adverse environmental effects.
Techniques for the delivery of pressurized contents in the form of an aerosol comprising therapeutic compositions, e.g., aerosol sprays of fine particles of liquid and/or solid compositions that contain therapeutic agents, are also well known and have seen many improvements. For example, conventional devices for delivering aerosolized medication for inhalation by a patient include metered dose inhalers (MDI). Such devices are designed to afford proper coordination of the delivery of a dose of therapeutic agent with inhalation by a patient to allow the proper dose of the therapeutic agent to be drawn into the patient's bronchial passages. There are currently also propellant-free dry powered inhalers on the market, but such devices have known disadvantages, including an inability to deliver more than about 10% of the inhaled therapeutic agent to the distal regions of the lung (e.g., the alveoli) where it can be efficiently absorbed into the blood stream, patients being unable to inhale rapidly enough to use such devices properly, and loss of the therapeutic agent if the patient exhales through the device.
MDIs are the most commonly used and prescribed medication delivery systems used to deliver inhaled medications for treatment of a variety of conditions, including bronchodilator therapy. MDIs may be manually operated or breath-activated devices. Breath-activated MDIs provide a metered dose automatically when the patient's respiratory effort actuates the device. See, for example, U.S. Pat. Nos. 6,260,549; 4,648,393; 4,803,978; and 4,896,832. The key problems associated with breath-activated devices include: the patient's inspiration effort may not be sufficient to trigger the release of the metered dose either all or some of the time; and, the patient's inspiration effort may be sufficient to trigger release of the metered dose, but not sufficient to cause the medication to pass into the desired portion of the patient's airways. Such problems cause patient frustration and inconsistent or inadequate medicament delivery, and may lead to ineffective therapy.
While conventional MDIs provide tremendous benefit for bronchodilator, steroid, and other drug delivery, there are still several limitations and problems associated with MDIs that need to be addressed in order to improve patient compliance and overall patient care. For example, because proper use of manually operated MDIs requires the patient to perform several important steps, patient error often adversely effects delivery of the aerosol to the desired site and the patient does not receive the appropriate dose. Such errors include: lack of coordination between actuation of the device and inspiration; inadequate inspiratory flow; inadequate breath holding; and inadequate deep inhalation. In addition, patients are often required to agitate the contents of the container for 2-4 seconds immediately prior to use to fully mix the components, and are cautioned to use the MDI only within a certain temperature range (e.g., 15-30 degrees C.). While these problems can be addressed through patient education and training, such training is often still inadequate.
MDI design can also lead to problems of ineffective delivery and improper doses being administered. For young children and elderly patients, insufficient hand strength may result in inadequate manual pressure to actuate a device that requires a patient to simultaneously apply manual pressure to both the top and bottom of the device to activate it, or may result in a partial actuation, thereby delivering an insufficient dose. When a patient fails to receive the prescribed dose, she may not obtain the expected benefit and will then overuse the medication, thereby increasing the risk of adverse side effects. Conversely, failure to obtain the expected benefit may lead to the patient to stop taking the medication altogether. There thus exists a need for devices that are easy to actuate and which provide a way for patients to monitor their correct usage of the device, so as to improve patient compliance and treatment.
In addition, patients often unexpectedly run out of medication because they are unable to monitor or estimate the amount of medication remaining in the device at any given time. MDI manufacturers typically label the MDI or the MDI product insert with a maximum number of doses to be delivered, and the patient is cautioned that the MDI should be discarded when the prescribed number of doses has been dispensed, “even though the canister is not completely empty” (see, e.g., the package insert for Albuterol). Patients using MDI products are therefore forced to manually log the doses administered for each MDI and subtract the doses administered from the total guaranteed maximum number of doses in the new container in order to compute the remaining in the container. This method of computing the number of doses remaining in the container is inconvenient, and prone to patient-induced book keeping errors. Most importantly, this method of computing is inaccurate because the patient is, in effect, counting the number of MDI metering valve actuations while assuming that the prescribed dose of therapeutic agent is being dispersed and evacuated from the container upon each actuation. In fact, if some of the actuations occur when the ambient temperature is outside of the recommended parameters for the particular MDI, the dose administered would be either higher or lower than expected and the number of doses remaining in the container would be proportionally inaccurate. Specifically, high ambient temperature conditions lead to dispensing more therapeutic agent and low ambient temperature conditions cause less to be dispensed. Finally, foreign material obstructions in or near the metering valve or transfer channel may also reduce the amount of therapeutic agent received compared to that which was expected. In effect, the patient has no real knowledge of the number of doses remaining in the container and may leave home with an MDI that does not contain an adequate supply of therapeutic agent, which can have life-threatening consequences.
Several approaches to solving these problems have been described in the literature. For example, some health advocate organizations recommend directly measuring the amount of medication in the container by removing the container from the actuator and then immersing the container in water. An observation of full immersion purportedly indicates a full container; a partially surfaced but vertical orientation indicates that the container is about half full; an inclined, floating container indicates that the container is about one-fourth full; and a horizontal floating container indicates that the container is empty (see Palo Alto Medical Foundation, a Sutter Health Affiliate). Also, it is presumed that some patients may develop a qualitative feel for the amount of medication remaining in the container, as they must shake or agitate the contents before use. These methods are clearly unreliable, inaccurate, and thus may be dangerous.
Another response to these problems has been to monitor airflow through a portion of a metering device. For example, devices have been developed for dispensing therapeutic agents that use an inductive displacement transducer to monitor airflow across the dispensing part of the device to create an actuation profile that can be used by the patient to monitor correct usage of the device. In such devices, the transducer measures the relative proximity of the device container to the device housing. In another approach, the apparatus directly counts the number of doses expended from a MDI by using a pressure sensor and/or an electronic sensor and a microprocessor to detect pressure pulse/airflow in the transfer channel of the mouthpiece of the MDI. The microprocessor processes data reflective of the pressure pulse/airflow and displays the doses remaining. Still another approach involves a medication dispenser that uses an actuation-indicator, employed as an add-on to an inhalation device, for detecting movement of the inhalation device container relative to the inhalation device housing. Breath-activated inhalers that employ a microprocessor to control activation and medication release based on flow rate and time interval from start of inspiration have also been developed. Such devices reportedly allow for optimal delivery of medication upon each activation. Another type of therapeutic agent dispenser utilizes two transceivers to provide for a two-way transfer of data to allow the patient to monitor dose counts and correct usage.
As those in the art will appreciate, the foregoing approaches to improving aerosol delivery devices such as MDIs measure conditions in the transfer channel to derive doses remaining in the container. While such approaches have advanced the technology, there clearly still exists a need for devices that provide the capability to allow patients to more accurately determine the quantity of pressurized contents in the container at any given time. Devices capable of directly measuring the quantity of contents remaining in the container address this shortcoming, as described below.